DMD/BMD: Taking a Closer Look at Ataluren

PTC Therapeutics, a South Plainfield, N.J., biopharmaceutical company, has announced findings that reflect the company's closer look at a large-scale trial of its experimental drug ataluren.

The additional results, presented April 16 at the American Academy of Neurology  meeting in Toronto, show that trial participants who took the lower dose of ataluren did better on a six-minute walking test than did participants who took the placebo or higher dose.

The new findings were presented by child neurologist Brenda Wong, a study investigator and director of the MDA clinic at Cincinnati Children’s Hospital.

PTC, in partnership with Genzyme, a Cambridge, Mass., biotechnology company, has been developing ataluren as a possible treatment for people with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) who have premature stop codon mutations in the gene for the muscle protein dystrophin. MDA has supported PTC for development of ataluren.

As was reported in March 2010 (see Ataluren Results Disappointing), an early analysis of the trial results suggested that there were no significant differences in the walking distance of patients treated with a high dose of ataluren, a low dose of ataluren, or a placebo. The trial’s primary measure of the drug’s effectiveness was a change in walking ability as shown by a change in the distance walked in six minutes.

About ataluren

Ataluren (formerly called PTC124) is designed to coax cells to ignore ("read through") premature stop codon mutations (also known as "nonsense" mutations) that stop cells from synthesizing a protein before all the genetic instructions have been processed.

Ataluren, it is hoped, will encourage cellular read-through of premature stop codon mutations and increase production of functional dystrophin in muscle tissue. An absence of dystrophin results in DMD, and a partial absence results in BMD.

About the new findings

This phase 2b trial of ataluren included 174 boys and young men ages 5 to 20 years at 37 sites in 11 countries. Through gene sequencing analysis, all trial participants were known to have DMD or BMD due to a premature stop codon mutation in the dystrophin gene.

Participants were randomly assigned to receive a placebo, low-dose ataluren or high-dose ataluren for 48 weeks (about a year).

The greater walking distance seen among patients receiving low-dose ataluren compared to patients receiving placebo was generally consistent regardless of age, use of corticosteroids (such as prednisone), or walking ability at the beginning of the study, investigators said.

At the end of the 48-week trial, patients in the high-dose group had a decrease in their six-minute walking distance by 42 meters (138 feet). Because of the natural progression of the disorder, the patients in the placebo group also had a decrease of 42 meters. By contrast, those on the low dose of ataluren had a decrease in their walking distance by only 13 meters (43 feet).

Wong stated that investigators were working to complete analyses of dystrophin levels in muscle fibers.

The dose-related findings obtained on closer examination of trial data, as well as the results of ongoing analyses of the data, could mean further development of ataluren for DMD/BMD, the company said.

For specifics about the trial results, please read the Summary of Ataluren Phase 2b Clinical Trial Results and Update on Ataluren Data, added to PTC's Web site by the company May 3, 2010.

Meaning for people with DMD or BMD

PTC researchers say they will continue to analyze the data from the phase 2b ataluren trial to see why patients receiving low-dose ataluren experienced better outcomes than those receiving high-dose ataluren. As these analyses are completed PTC and Genzyme expect to present new results later in 2010.

People with DMD/BMD resulting from premature stop codons should not give up hope for ataluren. There may yet be possibilities for this drug and others that coax cells to read through this type of genetic mutation.

For information as it becomes available, watch the MDA website and the PTC Therapeutics website.

Editor's note: This story was updated April 20 and May 3, 2010, with additional information provided by PTC Therapeutics.

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